Plasmacytoid dendritic cells (PDCs) are a subtype of dendritic cells (DCs) defined largely by their unique capacity to secrete type-I interferons in response to antigen. Although it has been proposed that the specialized functional attributes of PDCs are dictated by their development, little is known regarding the cellular or molecular basis for PDC ontogeny. We have characterized a novel mouse mutant that exhibits a marked reduction in the frequency and absolute number of splenic PDCs with normal frequencies of B and T cells, non-lymphoid blood cells, and other DC subsets. These mice also lack a bone marrow progenitor population shown here and to express several lymphoid-associated genes including Rag-2 and differentiate into DCs in culture. We propose several experiments to further characterize these putative PDC precursors and to elucidate the developmental origins of dendritic cells and the cytokines that regulate their development. Specifically, we propose to: 1. Determine the potential of a series of very early lymphoid progenitor populations to generate PDCs in vivo; 2. Determine the actual contribution of Rag-2+ lymphoid progenitors to each peripheral DC subset including PDCs; and 3. Identify cytokines that can redirect early B cell progenitors into the DC lineage in vitro and in vivo.